This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib [AZD1775]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence / absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+AZD6738 and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.

Inclusion Criteria

Informed consent prior to any study specific procedures.

Male or female ≥18 years of age.

Progressive cancer at the time of study entry.

Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations

5. Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting.

Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.

At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.

Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).

ECOG PS 0-1 within 28 days of randomisation.

Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).

Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks.

Exclusion Criteria

Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.

More than 2 prior lines of cytotoxic chemotherapy for metastatic disease (prior treatments with hormonal, non-hormonal, biologics or the combination of an aromatase inhibitor and everolimus are not counted as a prior line of therapy).

Previous randomisation in the present study.

Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless less than 3 weeks duration and at least 12 months has elapsed between the last dose and randomization).

Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation. The minimum washout period for immunotherapy shall be 42 days.

Patients with second primary cancer (exceptions defined in the protocol).

Any of the following cardiac diseases currently or within the last 6 months: unstable angina pectoris, congestive heart failure ≥ Class 2 as defined by the New York Heart Association, acute myocardial infarction, conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible), significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).

Concomitant use of known strong or moderate cytochrome P (CYP) 3A inhibitors, strong or moderate CYP3A inducers, or sensitive CYP3A4 substrates or CYp3A4 substrates with a narrow therapeutic index.

San Antonio

This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess
the efficacy and safety of olaparib monotherapy versus olaparib in combination with an
inhibitor of ATR (AZD6738) and olaparib monotherapy versus olaparib in combination with an
inhibitor of WEE1 (adavosertib) in second or third line setting in patients with TNBC
prospectively stratified by presence/absence of qualifying tumour mutation in genes involved
in the HRR pathway.
Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous
in a 28-day cycle, Arm 2: AZD6738 Days 1-7 with olaparib continuous in a 28-day cycle or Arm
3: adavosertib Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. Following the
ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib
treatment arm across all biomarker strata. Following closure of this arm the randomisation
ratio will be 1:1 to olaparib monotherapy or AZD6738+olaparib. Patients who were receiving
treatment with adavosertib+olaparib treatment were offered the opportunity to continue
treatment on olaparib monotherapy at the approved dose (300 mg bd).
The study subject population will be divided into Stratum A (patients with mutations in BRCA1
or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with
mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and
no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of
the HRR genes). Within each stratum A, B and C, there will be further stratification by
whether the patient received prior platinum-based therapy.
In the olaparib monotherapy treatment arm as well as in the AZD6738+olaparib treatment arm,
patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib
tablets will be taken at the same time each day, approximately 12 hours apart with one glass
of water (approximately 250 mL). In the adavosertib+olaparib treatment arm, patients will be
given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and adavosertib 150 mg bd from Day
1 to Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. AZD6738 will be
supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered
AZD6738 od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg
of AZD6738 tablets will be taken at the same time on each day of dosing with approximately
250 mL of water. Adavosertib will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100
mg, or 200 mg of drug substance. Adavosertib will be taken with approximately 250 mL of water
approximately 2 hours before or 2 hours after food. Olaparib, AZD6738 and adavosertib will be
provided by AstraZeneca.
Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient
populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non
HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for
PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5
patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and
Non HRRm patient populations. Tumour and germline mutation status will be analysed only in
the all patient population. PK outcome measures will be analysed only in the all patient
population. Blinded Independent Central Review (BICR) of radiological imaging data will be
carried out using RECIST version 1.1 and Investigator assessments will also be analysed for
sensitivity purposes.